1. Field of the Invention
The present invention also relates to markers and chromosomal amplification indicating in vivo drug resistance. More specifically, the present invention relates to using cancer markers and chromosomal region analyses for the prediction of patient outcome in ovarian cancer patients.
The present invention also relates to markers and therapeutics targeting in vivo drug resistance. More specifically, the present invention relates to the diagnosis and treatment using cancer markers and therapeutics which target drug resistance in ovarian cancer patients with low survival rates.
2. Related Art
The rapid and nearly inevitable onset of resistance in ovarian cancer has stimulated the evaluation of numerous alternative therapeutic agents. Those showing activity in ovarian cancer whose disease has relapsed after therapy with platinum and a taxane include doxil, topotecan, gemcitabine vinorelbine, etoposide and oxali platin (Harries, M. & Gore, M. Part II: chemotherapy for epithelial ovarian cancer-treatment of recurrent disease. Lancet Oncol 3, 537-45 (2002); Eltabbakh, G. H. & Awtrey, C. S. Current treatment for ovarian cancer. Expert Opin Pharmacother 2, 109-24 (2001)). In addition, advances in understanding the biology of ovarian cancer have led to the identification of cell cycle regulators, growth factor receptors, signal transduction pathways and angiogenic mechanisms that differ in normal and malignant cells. A number of targeted agents have entered clinical trials including small molecular weight inhibitors, monoclonal antibodies, and antisense and gene therapy (See, H. T., Kavanagh, J. J., Hu, W. & Bast, R. C. Targeted therapy for epithelial ovarian cancer: current status and future prospects. Int J Gynecol Cancer 13 (2003); Seiden, M. V. Ovarian cancer. Oncologist 6, 327-32 (2001)). However, most of these compounds do not specifically attack mechanisms leading to resistance.
Ovarian cancer remains the most lethal gynecologic cancer in the United States. Approximately twelve of every thousand women in this country will develop ovarian cancer in their lifetime and of these, nine or ten will succumb to the disease (American Cancer Society: Cancer Facts and Figures (URL:<http://www.cancer.org>). 2002). Most ovarian cancers are detected at an advanced stage, which contributes to the lethality. Current clinical management strategies for advanced ovarian cancers typically involve surgical reduction followed by platinum plus taxane based therapies (See Johnston, S. R. Ovarian cancer: review of the National Institute for Clinical Excellence (NICE) guidance recommendations. Cancer Invest 22, 730-42 (2004); Sandercock, J., Parmar, M. K., Torri, V. & Qian, W. First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence. Br J Cancer 87, 815-24 (2002); Harries, M. & Gore, M. Part II: chemotherapy for epithelial ovarian cancer-treatment of recurrent disease. Lancet Oncol 3, 537-45 (2002); and Harries, M. & Gore, M. Part J: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. Lancet Oncol 3, 529-36 (2002)). Most platinum compounds produce DNA cross-links (Bose, R. N. Biomolecular targets for platinum antitumor drugs. Mini Rev Med Chem 2, 103-11 (2002)) thereby inducing an apoptotic response via death receptor mechanisms as well as mitochondrial pathways (Boulikas, T. & Vougiouka, M. Cisplatin and platinum drugs at the molecular level. (Review). Oncol Rep 10, 1663-82 (2003); Giaccone, G. Clinical perspectives on platinum resistance. Drugs 59 Suppl 4, 9-17; discussion 37-8 (2000)). Taxanes, on the other hand, inhibit cell proliferation and trigger apoptotic responses by stabilizing otherwise dynamic microtubules that are important for centrosome and mitotic spindle function (Abal, M., Andreu, J. M. & Barasoain, I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets 3, 193-203 (2003)). Unfortunately, response rates are variable and most patients eventually develop resistance to these therapies (Harries, M & Gore, M., Lancet Oncol 3, 529-45 (2002); Boulikas, T. & Vougiouka, M., Oncol Rep 10, 1663-82 (2003); and van der Burg, M. E. Advanced ovarian cancer. Curr Treat Options Oncol 2, 109-118 (2001)). It is an objective thereforeto identify the subset of patients with the lowest survival rate (i.e. survive less than 24 months) on these therapies and to develop therapeutic strategies specifically targeted against the molecular lesions in their tumors.
A more promising approach in the long term is likely to attack the pathways leading to resistance. Numerous studies have suggested that both proliferative and anti-apoptotic pathways may be important in the onset and maintenance of chemoresistance (see review by Frazier et al., Chemoresistance in human ovarian cancer: the role of apoptotic regulators. Reprod Biol Endocrinol 1, 66 (2003)). Pathways implicated in apoptosis include the death receptor family, the PI3K/AKT cell survival pathway, FAK/β-integrin signaling, prohibitin, XIAP, and p53 mediated damage response. Novel agents designed to counter these resistance mechanisms are being explored (Vasey, P. A. Resistance to chemotherapy in advanced ovarian cancer: mechanisms and current strategies. Br J Cancer 89 Suppl 3, S23-8 (2003)). Our understanding of the p53 damage surveillance machinery is most well developed and agents targeting tumors lacking p53 function are well along in clinical evaluations and show substantial activity (Wolf, J. K. et al. A phase I study of Adp53 (INGN 201; ADVEXIN) for patients with platinum- and paclitaxel-resistant epithelial ovarian cancer. Gynecol Oncol 94, 442-8 (2004); Seemann, S., Maurici, D., Olivier, M., de Fromentel, C. C. & Hainaut, P. The tumor suppressor gene TP53: implications for cancer management and therapy. Crit. Rev Clin Lab Sci 41, 551-83 (2004)). However, insufficient evidence now exists to identify the apoptosis-suppressing genes that might be most effectively targeted in specific platinum/taxane treated patients.
One way to identify high priority apoptosis-suppressing genes is to identify recurrent aberrations involving genome sequence, copy number and/or gene expression that are associated with reduced survival duration. Markers for these genes can then be developed to detect aggressive cancers and inhibitors of these genes can be developed to treat these cancers. Genomic, epigenomic and gene expression changes in ovarian cancers that are associated with reduced survival duration reported recently include: (a) elevated/altered expression of COX-2 expression, p53 and SMAD4 (Erkinheimo, T. L. et al. Elevated cyclooxygenase-2 expression is associated with altered expression of p53 and SMAD4, amplification of HER-2/neu, and poor outcome in serous ovarian carcinoma. Clin Cancer Res 10, 538-45 (2004)), (b) reduced interferon gamma expression (Marth, C. et al. Interferon-gamma expression is an independent prognostic factor in ovarian cancer. Am J Obstet Gynecol 191, 1598-605 (2004)), (c) increased expression of focal adhesion kinase (FAK)(Sood, A. K. et al. Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am J Pathol 165, 1087-95 (2004)) (d) high bikunin expression (Tanaka, Y. et al. Reduced bikunin gene expression as a factor of poor prognosis in ovarian carcinoma. Cancer 98, 424-30 (2003)), (e) p16 methylation (Katsaros, D. et al. Methylation of tumor suppressor gene p16 and prognosis of epithelial ovarian cancer. Gynecol Oncol 94, 685-92 (2004)) and over expression of RAB25 (Cheng, K. W. et al. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med 10, 1251-6 (2004)). These studies have been guided by biological insights into the molecular events that are associated with ovarian cancer progression and provide information that may be used to develop useful prognostic markers. They are limited, however, since they do not provide information about the relative importance of these markers.
Relative importance has been assessed by others to identify aberrations that are most strongly associated with poor outcome in ovarian cancer using tumor transcription profiling and array technology. Published studies so far include a study that identified 182 hypermethylated CpG sequences associated with poor outcome (Wei, S. H., Brown, R. & Huang, T. H. Aberrant DNA methylation in ovarian cancer: is there an epigenetic predisposition to drug response? Ann N Y Acad Sci 983, 243-50 (2003)) and a gene expression profiling study that reported an 115-gene signature Ovarian Cancer Prognostic Profile (OCPP) associated with short survival duration (Spentzos, D. et al. Gene expression signature with independent prognostic significance in epithelial ovarian cancer. J Clin Oncol 22, 4648-58 (2004)).
One of the inventors with others have also described in U.S. Pat. No. 6,268,184 that the identification of chromosomal abnormalities and amplification in the human 20q13 chromosomal region can be used as a prognostic indicator of breast cancer.